Abstract: Retinal degenerative diseases, characterized by photoreceptor cell loss, are currently the leading cause of incurable blindness in the western world. As the intrinsic regenerative capacity of the mammalian retina is extremely limited, the only viable treatment option for people suffering from photoreceptor cell loss is cellular replacement. Although a range of data suggests that the use of stem cells to achieve such a goal is now feasible, selection of the most suitable cell type and the optimal delivery method is critical. Due to patient specific compatibility and reduced ethical concern, the induced pluripotent stem cell (iPSC), initially produced via genetic reprogramming of dermal fibroblasts to pluripotency using the 4 transcription factors Oct4, Sox2, KLF4, and c-Myc, is of interest. However, to be a source of photoreceptor precursor cells for clinical application, elimination of the potentially tumorogenic oncogenes c-Myc and KLF4 from the reprogramming protocol must be achieved. In previous attempts to do so it has become evident that developmentally immature cells, such as umbilical cord fibroblasts that are highly accessable and still patient specific, should be used. Yet, as promising as stem cell transplantation may be, problems related to cellular survival, migration and functional tissue-specific integration remain. This can predominantly be accounted for by a lack of donor cell support following bolus cell injection. As such, transplanting cells on a bioengineered cellular support system to circumvent this issue will be beneficial. We propose to produce an umbilical cord iPSC-derived photoreceptor precursor/biodegradable polymer composite construct, designed to mimic the native outer photoreceptor layer of the retina, to be used for transplantation. This technology will be tested for its ability to induce functional regeneration and restoration of vision in a large animal model of retinal degeneration. ) Public Health Relevance: Retinal degenerative diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), which result in photoreceptor cell loss, are currently the leading cause of incurable blindness in the western world. As the retina is incapable of regenerating following injury or disease, patients stricken by these disorders will ultimately require therapies focused on cellular replacement. Successful completion of the proposed study, which aims to combine state-of-the-art stem cell, tissue engineering and transplantation technologies, would justify the initiation of clinical trials and development of a restorative therapy for human retinal degenerative disorders.